Separable roles for<i>Mycobacterium tuberculosis</i>ESX-3 effectors in iron acquisition and virulence

Tufariello, Jo Ann M.; Chapman, Jessica R.; Kerantzas, Christopher A.; Wong, K. W.; Vilchèze, Catherine; Jones, Christopher M.; Cole, Laura E.; Tinaztepe, Emir; Thompson, Victor; Fenyö, David; Niederweis, Michael; Ueberheide, Beatrix; Philips, Jennifer A.; Jacobs, William R.

doi:10.1073/pnas.1523321113

Cited by 173 publications

(243 citation statements)

References 79 publications

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“…ESX-3 proteins: EsxG and EsxH are associated with the (proline-glutamic acid, proline-proline-glutamic acid) PE and PPE secretion [52]. The EsxG and EsxH heterodimer, which harms macrophage phagosome maturation, is secreted by the ESX-3 system [53] and inhibits the endosomal-sorting complex required for transport (ESCRT) impairing MTB antigen-specific CD4 + activation by macrophages and DC [54].…”

Section: Esx-3mentioning

confidence: 99%

Virulence Factors and Pathogenicity of Mycobacterium

Echeverría-Valencia¹,

Flores-Villalva²,

Espitia³

2018

Mycobacterium - Research and Development

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Virulence, is referred as the ability of a pathogen to cause disease, and for mycobacteria it depends on their ability to reside within host cells and evade the microbicidal mechanisms of macrophages. The outcome of tuberculosis (TB) infection is highly variable and it seems that the closest relationship between the Mycobacterium genre and humans has shaped the mycobacterial genome to encode bacterial factors that reflects a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity causing disease even in fully immunocompetent host. Although Mycobacterium tuberculosis (MTB) does not have classical virulence factors, it has described many virulence-associated genes and virulence lifestyle genes from Mycobacterium tuberculosis complex (MTBC). In this chapter, we describe the most important gene/molecule involved in the host defense modulation response, also the plethora of strategies to evade immune mechanisms of macrophage. We review the main genes whose inactivation in the mycobacterial genome leads to a measurable loss in virulence in the different validated TB models.

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Section: Esx-3mentioning

confidence: 99%

Virulence Factors and Pathogenicity of Mycobacterium

Echeverría-Valencia¹,

Flores-Villalva²,

Espitia³

2018

Mycobacterium - Research and Development

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“…Analysis of the IdeR, Zur, and MntR regulons demonstrated that the esx-3 locus, which encodes the ESX-3 type 7 secretion system (T7SS), is transcriptionally regulated by iron, zinc, and manganese (15-17). ESX-3 is required for the utilization of iron from mycobactin in both nonpathogenic Mycobacterium smegmatis and in M. tuberculosis, although the mechanism by which ESX-3 promotes iron acquisition is not understood (18)(19)(20). In M. tuberculosis, ESX-3 is essential under standard laboratory conditions; growth can be restored to esx-3 mutants by the addition of exogenous mycobactin (20).…”

Section: T He Intracellular Pathogen Mycobacterium Tuberculosis Survimentioning

confidence: 99%

Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

et al. 2016

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bMore people die every year from Mycobacterium tuberculosis infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen Mycobacterium smegmatis, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In M. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With M. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the esx-3 locus to these metals. While iron regulated the esx-3 expression in both M. tuberculosis and M. smegmatis, there is a significant difference in the dynamics of this regulation. In M. smegmatis, the esx-3 locus behaved like other iron-regulated genes such as mbtB. In M. tuberculosis, both iron and zinc modestly repressed esx-3 expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of M. tuberculosis with macrophages, leading to impaired intracellular M. tuberculosis survival. Our findings detail the regulatory differences of esx-3 in M. tuberculosis and M. smegmatis and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in M. tuberculosis. T he intracellular pathogen Mycobacterium tuberculosis survives within phagocytic immune cells such as macrophages and dendritic cells (1).M. tuberculosis evades degradation by the endolysosomal pathway, growing in an early endosome-like compartment or escaping into the cytosol (2, 3). Acidified lysosomes are just one obstacle for the bacilli to overcome as the host also regulates metals such as iron, zinc, copper, and manganese to create an uninhabitable microenvironment (4). These metals are essential but at the same time can be toxic, so both host and pathogen tightly regulate them. For example, macrophages can increase zinc levels in M. tuberculosis-containing phagosomes to induce toxicity (5). Calprotectin, on the other hand, is released at sites of infection to bind and withhold zinc and manganese from bacteria (6). Similarly, host iron is bound to glycoproteins such as transferrin and lactoferrin, and during infection the host further limits available iron by reducing plasma iron levels via ferroportins (7-9). In addition, lipocalin 2-mediated sequestration of iron has been shown to be an important antimycobacterial innate immune response (10). To compete for iron, M. tuberculosis produces siderophores, mycobactin and carboxymycobactin, which are highaffinity iron chelators (11). Since iron is a strong redox catalyst that can be toxic to cel...

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“…First, ESX-3 systems promote metal homeostasis (32,(70)(71)(72)(73)(74). Although ESX-3 promotes siderophore-mediated iron and zinc acquisition in M. tuberculosis (70,71), in M. smegmatis, the ESX-3 system promotes iron homeostasis only (71,72).…”

mentioning

confidence: 99%

“…Although ESX-3 promotes siderophore-mediated iron and zinc acquisition in M. tuberculosis (70,71), in M. smegmatis, the ESX-3 system promotes iron homeostasis only (71,72). Underscoring the importance of metal homeostasis, ESX-3 genes are essential in M. tuberculosis; survival in the absence of ESX-3 genes can be restored with metal supplementation (73). Second, the ESX-3 system promotes virulence of M. tuberculosis (73,75).…”

mentioning

confidence: 99%

“…Underscoring the importance of metal homeostasis, ESX-3 genes are essential in M. tuberculosis; survival in the absence of ESX-3 genes can be restored with metal supplementation (73). Second, the ESX-3 system promotes virulence of M. tuberculosis (73,75). The ESX-3 substrate EsxH directly interacts with host endosomal sorting complexes required for transport (ESCRT) machinery, preventing phagosomal maturation and antigen presentation during macrophage infection with M. tuberculosis (75,76).…”

mentioning

confidence: 99%

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Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?

Bosserman

Champion

2017

J Bacteriol

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Mycobacterial 6-kDa early secreted antigenic target (ESAT-6) system (ESX) exporters transport proteins across the cytoplasmic membrane. Many proteins transported by ESX systems are then translocated across the mycobacterial cell envelope and secreted from the cell. Although the mechanism underlying protein transport across the mycolate outer membrane remains elusive, the ESX systems are closely connected with and localize to the cell envelope. Links between ESX-associated proteins, cell wall synthesis, and the maintenance of cell envelope integrity have been reported. Genes encoding the ESX systems and those required for biosynthesis of the mycobacterial envelope are coregulated. Here, we review the interplay between ESX systems and the mycobacterial cell envelope.

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Separable roles forMycobacterium tuberculosisESX-3 effectors in iron acquisition and virulence

Cited by 173 publications

References 79 publications

Virulence Factors and Pathogenicity of Mycobacterium

Virulence Factors and Pathogenicity of Mycobacterium

Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?

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